No mutations were identified.

Transcription

1 Hereditary High Cholesterol Test ORDERING PHYSICIAN PRIMARY CONTACT SPECIMEN Report date: Aug 1, 2017 Dr. Jenny Jones Sample Medical Group 123 Main St. Sample, CA Kelly Peters Sample Medical Group 123 Main St. Sample, CA Type: Saliva Barcode: Collected: Jul 15, 2017 Received: Jul 17, 2017 No mutations were identified. This means no pathogenic or likely pathogenic mutations associated with Familial Hypercholesterolemia (FH) were identified in any of the genes analyzed. FH is a hereditary disorder associated with very high levels of cholesterol (hypercholesterolemia) at an early age, specifically a type of cholesterol called LDL-C. High cholesterol can impact your risk of coronary heart disease, which can lead to heart attack and stroke. NOTES ABOUT YOUR RESULT A negative test result for mutations that cause FH does not mean that you don t have high cholesterol or a clinical diagnosis of FH. Environment and lifestyle, as well as family history without a known genetic link, can have a large influence on your cholesterol. Work with your healthcare provider to understand your cholesterol and manage it if needed. GENES ANALYZED The genes below were analyzed, and no pathogenic or likely pathogenic mutations associated with Familial Hypercholesterolemia were identified. Please see the test methodology and limitations section for additional information. APOB, LDLR, PCSK9 REVIEWED BY Tom Sample, MD, Pathologist Date 1 / 8

2 Risk and Family Information LIFETIME RISK among US men Average risk among US men to develop coronary heart disease in their lifetime. Risk may vary because of factors such as diet and physical activity level, among others. CORONARY HEART DISEASE 1 60% 45% Normal cholesterol Borderline cholesterol High cholesterol 30% 15% 0% Risk at age: FAMILY Consider sharing your results with relatives who may also benefit from genetic testing. A few key points to remember: Your negative result significantly lowers the chance that you have an inherited mutation associated with Familial Hypercholesterolemia (FH). It is still possible for your relatives to have a mutation that you did not inherit. They may benefit from their own genetic testing, especially those who have had high cholesterol. If any of your relatives has a mutation, there is a 50% chance that their siblings and children also have the same mutation. A father and mother are equally likely to pass on a mutation. Sons and daughters are equally likely to inherit a mutation if one of their parents has it. If you learn that a relative of yours has a mutation, contact a Color genetic counselor to learn how that information may impact your risk assessment and interpretation of results. 1 Lloyd-Jones DM, Wilson PW, Larson MG, et al. Lifetime risk of coronary heart disease by cholesterol levels at selected ages. Arch Intern Med. 2003;163(16): / 8

3 Know Your Screening Guidelines Below is a summary of the current screening guidelines from the American Heart Association (AHA). These guidelines are for men with the same risk of coronary heart disease as the average US man. Your healthcare provider may use the AHA Guidelines to help create a customized screening plan for you. CORONARY HEART Starting at age 20: DISEASE 2 Blood pressure checked at each regular healthcare visit or at least once every 2 years Cholesterol levels checked every four to six years Weight and Body Mass Index (BMI) checked at each regular healthcare visit Waist circumference checked as needed to help evaluate cardiovascular risk Discussion of risk factors such as smoking, physical activity, and diet at each regular healthcare visit Starting at age 45: Blood sugar (glucose) test every three years These recommendations may change if you have an elevated risk for heart attack or stroke due to other risk factors. GENERAL HEART HEALTH RECOMMENDATIONS FOR ALL INDIVIDUALS 3 Don t smoke and avoid second-hand smoke Treat high blood pressure if you have it Eat foods that are low in saturated fat, trans fat, sodium (salt) and added sugars Be physically active Reach and maintain a healthy weight Control your blood sugar if you have diabetes Get regular medical check-ups Take medicine as prescribed 2 Goff DC, Lloyd-jones DM, Bennett G, et al ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S Eckel RH, Jakicic JM, Ard JD, et al AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S / 8

4 Common Questions GENERAL QUESTIONS What does a negative test result mean? A negative result means no pathogenic or likely pathogenic genetic variants associated with Familial Hypercholesterolemia (FH) were identified in any of the genes analyzed. This result does not mean you don t have high cholesterol or a clinical diagnosis of FH, and does not eliminate your risk of developing coronary heart disease. You may still be at increased risk of high cholesterol due to other factors, mutations not detected by current technology, or mutations in other genes. Does this result mean I m not at risk of developing high cholesterol? No, the absence of mutations does not mean that you will not develop high cholesterol. Because cholesterol levels can be affected by many non-genetic factors, a negative result does not mean high cholesterol can t happen. Eating foods high in saturated fats and cholesterol increase the levels of cholesterol, which increases the chances of coronary heart disease. The risk of coronary heart disease is higher in people who have high cholesterol, are overweight, are not physically active, smoke and drink excessive amounts of alcohol, and in people with diabetes. Factors we cannot control that affect cholesterol levels include age, sex, and other genetic factors. Older individuals typically have higher levels of cholesterol and a higher risk of heart disease. In addition, not all of the genes related to having high cholesterol levels are known or included on the Color test. You should continue to follow the screening and prevention advice of your healthcare team, or schedule an appointment with a Color genetic counselor if you have questions. Who will see these test results? Your results are available to you and the healthcare provider who ordered your test, as well as any additional healthcare providers you designated. Your results will not be sent by Color to your insurance company, employer, or any other healthcare provider without your explicit request. Should I share my results with my healthcare provider? Color recommends you share your results with your provider. Sharing your results allows your provider to guide you to appropriate resources and discuss tailored options for screening and monitoring of cholesterol levels. Are there any protections against discrimination based on these results? In 2008, a federal law called the Genetic Information Non-Discrimination Act (GINA) was passed. Under the terms of GINA, medical insurance companies and employers are prohibited from discriminating against individuals on the basis of genetic information. GINA defines genetic information as including not only genetic test results, but also family history, and the fact that genetic testing occurred. The terms of GINA specify that insurance companies cannot raise rates, cancel a plan, or determine eligibility because of genetic testing. Employers also are prohibited from making hiring, firing, or promotion decisions based on genetic testing. The terms of GINA carry exceptions. For example, an exception might include employers with fewer 4 / 8

5 GENERAL QUESTIONS (Continued) than 15 employees and those with military insurance. Additionally, GINA does not extend to life, disability, or long-term insurance companies. Some states may have protections regarding discrimination from these types of insurance. Individuals may consider purchasing these policies prior to undergoing genetic testing. ABOUT FAMILY What do my results mean to my relatives and do any of them need to consider genetic testing? Though you do not carry a mutation associated with FH, it is possible that your relatives have one that you did not inherit. The only way for them to know whether or not they have such a mutation is for them to undergo genetic testing. Genetic testing can be particularly informative for individuals in the family who have high cholesterol. Please schedule an appointment with a Color genetic counselor for specific recommendations about testing tailored to your family. Should I talk with my relatives about my result? You are encouraged to share these results with your relatives. Knowing this information may help them decide whether genetic testing is right for them. Relatives with high cholesterol may especially find this information useful. However, keep in mind that not everyone wants to know their genetic status and genetic testing is a personal decision. 5 / 8

6 TEST METHODOLOGY AND LIMITATIONS Methodology This test is designed to assess clinically relevant mutations in genes associated with Familial Hypercholesterolemia. Genomic DNA is extracted from a saliva or peripheral blood sample using standard methods. For the genes analyzed, Next Generation Sequencing libraries compatible with the Illumina platform are generated and enriched via a custom designed Agilent SureSelect bait library. DNA fragments enriched from these genes are retrieved and analyzed using 2x150 paired-end sequencing with an Illumina NextSeq 500 instrument. After alignment to reference genome GRCh37.p12 (hg19), low quality and duplicate reads are removed and variants are identified using the GATK Haplotypecaller. This test detects single nucleotide substitutions (SNV), small insertions and deletions (indels) in the DNA coding sequences, nearby flanking regions (+/- 20bp) and known splice regions in the genes targeted by the Color panel. In addition, copy number variations (CNVs), large insertions and inversions overlapping coding exons, are reported. The Color test has >20X coverage for 100% of regions in our reportable range. The median coverage across our samples is >250X and our minimum acceptance criteria for depth is: >99% at >50X and 100% at 20X. Any exceptions to this are noted in the Limitations section. Variants are classified according to the standards and guidelines for sequence variant interpretation of the American College of Medical Genetics and Genomics (ACMG). Variant classification categories include pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. All variants are evaluated by a board certified medical geneticist or pathologist. Identified likely benign and benign variants are not reported. The presence of a VUS is always reported, and the details are available upon request. All VUS and likely pathogenic variants are reviewed bi-annually for updates in the scientific literature. As part of the Color service, we will attempt to recontact the provider and/or the person that was tested if any reported variant s classification changes. Clinically actionable variants (i.e. likely pathogenic and pathogenic) are confirmed using an alternative technology (Sanger sequencing, acgh or MLPA) in compliance with Color s internal protocols and relevant ACMG guidelines. For SNVs and indels, a confidence model (color.com/ variantconfidence) is used to identify high and low confidence variants. Low confidence variants, and structural variants (CNVs, insertions and inversions) are confirmed using an alternative technology. High confidence, clinically actionable variants that have been independently confirmed at least three times will not be submitted for further secondary confirmation. High confidence VUSs are reported without secondary confirmation. This test was developed and its performance characteristics determined by, a clinical laboratory accredited by the College of American Pathologists (CAP) and certified under the Clinical Laboratory Improvement Amendments (CLIA) to perform high-complexity testing (CAP # CLIA #05D ). This test has not been cleared or approved by the United States Food and Drug Administration (FDA). The FDA does not require this test to go through premarket FDA review. This test is used for clinical purposes. It should not be regarded as investigational or for research. Genes APOB*, LDLR**, PCSK9* 6 / 8

7 TEST METHODOLOGY AND LIMITATIONS (Continued) * Please see the Limitations section for more information. ** The promoter region is analyzed for CNVs. In addition, a small region of the promoter (LDLR, Chr19: ) is also analyzed for the presence of clinically relevant SNVs and indels. Limitations This test aims to detect all clinically relevant variants within the genes analyzed (defined above). The majority of these genes are assessed for variants within all coding exons (+/- 20bp in the nearby flanking regions). For PCSK9 gene exon 8, only the first 7bp of intron 8 are analyzed. In APOB, exon 1 is not analyzed. For the LDLR promoter region, the detection of deletions, duplications, and complex structural rearrangements may be limited. This test is not designed to detect chromosomal aneuploidy or complex rearrangements such as translocations. It also does not reliably detect mosaicism. The sensitivity to detect deletions and duplications in the range of bp, as well as those which deletion/duplication do not overlap more than 250bp of contiguous coding sequence, may be reduced. The presence of a large insertion may interfere with the chemistry used to target the genes of interest, which could decrease the detection sensitivity. In addition, the sequence and identity of a large insertion may not be completely resolved. Inversions including at least one coding exon will be detected only if the breakpoints are covered by the Color test. The sensitivity to detect variants in the vicinity of homopolymer regions may be reduced. Color only reports findings within the genes that are on the panel. It is important to understand that there may be variants in those genes that current technology is not able to detect. Additionally, there may be genes associated with Familial Hypercholesterolemia whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with Familial Hypercholesterolemia. Additionally, in the unlikely event a variant is detected that is associated with a disorder other than Familial Hypercholesterolemia, this information will not be included in the report. Genetic counseling and/or physician consultation may be warranted to ensure complete understanding of your test results. In very rare cases, such as circulating hematolymphoid neoplasm, allogeneic bone marrow transplant, or recent blood transfusion (within 7 days of testing), the results of germline DNA analysis may be complicated by somatic and/or donor mutations. DNA quality may be affected if a participant has received chemotherapy within the last 120 days. Disclaimers Color implements several safeguards to avoid technical errors, such as 2-dimensional barcoding and barcode scanning at several steps throughout the sequencing process. Color is not responsible for errors in specimen collection, transportation, and activation or other errors made prior to receipt at our laboratory. Due to the complexity of genetic testing, diagnostic errors, although rare, may occur due to sample mix-up, DNA contamination, or other laboratory operational errors. In addition, poor sample DNA quality and certain characteristics inherent to specific regions of an individual s genomic DNA may limit the accuracy of results in those regions. In the absence of an identified pathogenic or likely pathogenic mutation, standard risk models may be employed to determine potential risk of Familial Hypercholesterolemia and guidelines 7 / 8

8 TEST METHODOLOGY AND LIMITATIONS (Continued) displayed on this report. All risk estimation is approximate, sometimes cannot be specifically calculated, and is based on previously analyzed cohorts. Additionally, risk estimation may be incorrect if inaccurate personal or family history is provided. An elevated risk for Familial Hypercholesterolemia is not a diagnosis and does not guarantee that a person will develop the disease. Contact us free of charge at (844) with any questions. 8 / 8